Table of contents

Cell survival following exposure to spatially modulated beams, as created by intensity-modulated radiotherapy (IMRT), is investigated. In vitro experiments were performed using malignant melanoma cells (MM576) exposed to a therapeutic megavoltage photon beam. We compared cell survival in modulated fields with cell survival in uniform control fields. Three different spatial modulations of the field were used: a control 'uniform' field in which all cells in a flask were uniformly exposed; a 'quarter' field in which 25% of cells at one end of the flask were exposed and a 'striped' field in which 25% of cells were exposed in three parallel stripes. The cell survival in both the shielded and unshielded regions of the modulated fields, as determined by a clonogenic assay, were compared to the cell survival in the uniform field. We have distinguished three ways in which cell survival is influenced by the fate of neighbouring cells. The first of these (type I effect) is the previously reported classical Bystander effect, where cell survival is reduced when communicating with irradiated cells. We find two new types of Bystander effect. The type II effect is an observed increase in cell survival when nearby cells receive a lethal dose. The type III effect is an increase in the survival of cells receiving a high dose of radiation, when nearby cells receive a low dose. These observations of the Bystander effects emphasize the need for improved radiobiological models, which include communicated effects and account for the effects of modulated dose distribution.

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Intensity-modulated radiation therapy (IMRT) uses radiation beams of varying intensities to deliver varying doses of radiation to different areas of the tissue. The use of IMRT has allowed the delivery of higher doses of radiation to the tumor and lower doses to the surrounding healthy tissue. It is not uncommon for head and neck tumors, for example, to have large treatment widths that are not deliverable using a single field. In such cases, the intensity matrix generated by the optimizer needs to be split into two or three matrices, each of which may be delivered using a single field. Existing field-splitting algorithms used the pre-specified arbitrary split line or region where the intensity matrix is split along a column, i.e., all rows of the matrix are split along the same column (with or without the overlapping of split fields, i.e., feathering). If three fields result, then the two splits are along the same two columns for all rows. In this paper we study the problem of splitting a large field into two or three subfields with the field width as the only constraint, allowing for an arbitrary overlap of the split fields, so that the total MU efficiency of delivering the split fields is maximized. Proof of optimality is provided for the proposed algorithm. An average decrease of 18.8% is found in the total MUs when compared to the split generated by a commercial treatment planning system and that of 10% is found in the total MUs when compared to the split generated by our previously published algorithm.

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In the last few years, mathematically exact algorithms, including the backprojection-filtration (BPF) algorithm, have been developed for accurate image reconstruction in helical cone-beam CT. The BPF algorithm requires minimum data, and can reconstruct region-of-interest (ROI) images from data containing truncations. However, similar to other existing reconstruction algorithms for helical cone-beam CT, the BPF algorithm involves a backprojection with a spatially varying weighting factor, which is computationally demanding and, more importantly, can lead to undesirable numerical properties in reconstructed images. In this work, we develop a rebinned BPF algorithm in which the backprojection invokes no spatially varying weighting factor for accurate image reconstruction from helical cone-beam projections. This rebinned BPF algorithm is computationally more efficient and numerically more stable than the original BPF algorithm, while it also retains the nice properties of the original BPF algorithm such as minimum data requirement and ROI-image reconstruction from truncated data. We have also performed simulation studies to validate and evaluate the rebinned BPF algorithm.

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The deposition of gadolinium through ultrasound-induced blood–brain barrier (BBB) openings in the murine hippocampus was investigated. First, wave propagation simulations through the intact mouse skull revealed minimal beam distortion while thermal deposition simulations, at the same sonication parameters used to induce BBB opening in vivo, revealed temperature increases lower than 0.5 °C. The simulation results were validated experimentally in ex vivo skulls (m = 6) and in vitro tissue specimens. Then, in vivo mice (n = 9) were injected with microbubbles (Optison™; 25–50 µl) and sonicated (frequency: 1.525 MHz, pressure amplitudes: 0.5–1.1 MPa, burst duration: 20 ms, duty cycle: 20%, durations: 2–4 shots, 30 s per shot, 30 s interval) at the left hippocampus, through intact skin and skull. Sequential, high-resolution, T1-weighted MRI (9.4 Tesla, in-plane resolution: 75 µm, scan time: 45–180 min) with gadolinium (Omniscan™; 0.5 ml) injected intraperitoneally revealed a threshold of the BBB opening at 0.67 MPa and BBB closing within 28 h from opening. The contrast-enhancement area and gadolinium deposition path were monitored over time and the influence of vessel density, size and location was determined. Sonicated arteries, or their immediate surroundings, depicted greater contrast enhancement than sonicated homogeneous brain tissue regions. In conclusion, gadolinium was delivered through a transiently opened BBB and contained to a specific brain region (i.e., the hippocampus) using a single-element focused ultrasound transducer. It was also found that the amount of gadolinium deposited in the hippocampal region increased with the acoustic pressure and that the spatial distribution of the BBB opening was determined not only by the ultrasound beam, but also by the vasculature of the targeted brain region.

Subharmonic contrast imaging promises to improve ultrasound-imaging quality by taking advantage of an increased contrast to tissue signal. However, acoustic pressures beyond the subharmonic generation threshold using common ultrasound pulses may induce significant contrast microbubble destruction. In this work, a chirp excitation technique is presented to enhance the subharmonic emission from encapsulated microbubbles. Chirp signals with a center frequency of 5 MHz, variable frequency range and duration time are employed to drive microbubbles in numerical simulation and experimental studies. We provide a theoretical evaluation of the chirp excitation pressure threshold and the acoustic pressure dependence of subharmonic based on Church's model and demonstrate that the amplitude and axial resolution of the subharmonic can be optimized by proper selection of the frequency range and time duration of the chirp signal. Measurements are qualitatively in agreement with the simulation. Moreover, we demonstrate that chirp excitation may be able to improve the amplitude of the subharmonic component up to 22 dB over the pulse excitation. The chirp excitation technique could potentially be used for improving the subharmonic contrast imaging quality.

Quantitative image quality results in the form of the modulation transfer function (MTF), normalized noise power spectrum (NNPS) and detective quantum efficiency (DQE) are presented for nine full field digital mammography (FFDM) systems. These parameters are routinely measured as part of the quality assurance (QA) programme for the seven FFDM units covered by our centre. Just one additional image is required compared to the standard FFDM protocol; this is the image of an edge, from which the MTF is calculated. A variance image is formed from one of the flood images used to measure the detector response and this provides useful information on the condition of the detector with respect to artefacts. Finally, the NNPS is calculated from the flood image acquired at a target detector air kerma (DAK) of 100 µGy. DQE is then estimated from these data; however, no correction is currently made for effects of detector cover transmission on DQE. The coefficient of variation (cov) of the 50% point of the MTF for five successive MTF results was 1%, while the cov for the 50% MTF point for an a-Se system over a period of 17 months was approximately 3%. For four a-Se based systems, the cov for the NNPS at 1 mm⁻¹ for a target DAK of 100 µGy was approximately 4%; the same result was found for four CsI based FFDM units. With regard to the stability of NNPS over time, the cov for four NNPS results acquired over a period of 12 months was also approximately 4%. The effect of acquisition geometry on NNPS was also assessed for a CsI based system. NNPS data acquired with the antiscatter grid in place showed increased noise at low spatial frequency; this effect was more severe as DAK increased. DQE results for the three detector types (a-Se, CsI and CR) are presented as a function of DAK. Some reduction in DQE was found for both the a-Se and CsI based systems at a target DAK of 12.5 µGy when compared to DQE data acquired at 100 µGy. For the CsI based systems, DQE at 1 mm⁻¹ fell from 0.49 at 100 µGy to 0.38 at 12.5 µGy. For the a-Se units, there was a slightly greater reduction in average DQE at 1 mm⁻¹, from 0.53 at 100 µGy to 0.31 at 12.5 µGy. Somewhat different behaviour was seen for the CR unit; DQE (at 1 mm⁻¹) increased from 0.40 at 100 µGy to 0.49 at 12.5 µGy; however, DQE fell to 0.30 at 420 µGy. DQE stability over time was assessed using the cov of DQE at 1 mm⁻¹ and a target DAK of 100 µGy; the cov for data acquired over a period of 17 months for an a-Se system was approximately 7%. For comparison with conventional testing methods, the cov was calculated for contrast-detail (cd) data acquired over the same period of time for this unit. The cov for the threshold contrast results (averaged for disc diameters between 0.1 mm and 2 mm) was 6%, indicating similar stability.

Fluorescence diffuse optical tomography (FT) is an emerging molecular imaging technique that can spatially resolve both fluorophore concentration and lifetime parameters. In this study, we investigate the performance of a frequency-domain FT system for small inclusions that are embedded in a heterogeneous background. The results demonstrate that functional and structural a priori information is crucial to be able to recover both parameters with high accuracy. The functional a priori information is defined by the absorption and scattering maps at both excitation and emission wavelengths. Similarly, the boundaries of the small inclusion and different regions in the background are utilized as the structural a priori information. Without a priori information, the fluorophore concentration of a 5 mm inclusion in a 40 mm medium is recovered with 50% error, while the lifetime cannot be recovered at all. On the other hand, when both functional and structural information are available, the true lifetime can be recovered and the fluorophore concentration can be estimated only with 5% error. This study shows that a hybrid system that can acquire diffuse optical absorption tomography (DOT), FT and anatomical images in the same setting is essential to be able to recover the fluorophore concentration and lifetime accurately in vivo.

Image registrations that are based on similarity measures simply adjust the parameters of an appropriate spatial transformation model until the similarity measure reaches an optimum. The numerous similarity measures that have been proposed in the past are differently sensitive to imaging modality, image content and differences in the image content, selection of the floating and target image, partial image overlap, etc. In this paper, we evaluate and compare 12 similarity measures for the rigid registration. To study the impact of different imaging modalities on the behavior of similarity measures, we have used 16 CT/MR and 6 PET/MR image pairs with known 'gold standard' registrations. The results for the PET/MR registration and for the registration of CT to both rectified and unrectified MR images indicate that mutual information, normalized mutual information and the entropy correlation coefficient are the most accurate similarity measures and have the smallest risk of being trapped in a local optimum. The results of an experiment on the impact of exchanging the floating and target image indicate that, especially in MR/PET registrations, the behavior of some similarity measures, such as mutual information, significantly depends on which image is the floating and which is the target.

We investigate the heterogeneity of electrical conductivity as a new mechanism to stimulate excitable tissues via applied electric fields. In particular, we show that stimulation of axons crossing internal boundaries can occur at boundaries where the electric conductivity of the volume conductor changes abruptly. The effectiveness of this and other stimulation mechanisms was compared by means of models and computer simulations in the context of transcranial magnetic stimulation. While, for a given stimulation intensity, the largest membrane depolarization occurred where an axon terminates or bends sharply in a high electric field region, a slightly smaller membrane depolarization, still sufficient to generate action potentials, also occurred at an internal boundary where the conductivity jumped from 0.143 S m⁻¹ to 0.333 S m⁻¹, simulating a white-matter-grey-matter interface. Tissue heterogeneity can also give rise to local electric field gradients that are considerably stronger and more focal than those impressed by the stimulation coil and that can affect the membrane potential, albeit to a lesser extent than the two mechanisms mentioned above. Tissue heterogeneity may play an important role in electric and magnetic 'far-field' stimulation.

In this work, we propose a framework for calculating brachytherapy dose distributions in heterogeneous media. The approach taken includes analytical calculation of the primary dose, and separately treats contributions of the once-scatter photons and multiple-scatter photons to the total scatter dose. This paper focuses on the evaluation of the once-scatter dose, which is based on a micro-beam ray-tracing model developed by the authors that incorporates an accurate description of the physical scattering of photons (Compton and Rayleigh scattering) with considerable flexibility in accommodating diverse geometries in a heterogeneous medium. The accuracy of the ray-tracing model has been verified by comparing model-calculated once-scatter doses with corresponding Monte Carlo results. For a 22 keV, 27 keV and 300 keV point source in water containing a disc-shaped heterogeneity of whitlockite, stainless steel or lead, our calculated results for once-scatter doses are in excellent agreement with corresponding Monte Carlo results over a wide range of heterogeneity dimensions and positions. Our investigation also explores the differences between physical scattering and isotropic scattering in evaluating the once-scatter dose, and thus enables the domain of applicability of the latter to be assessed. An appropriate method for evaluating the multiple-scatter dose, which together with the micro-beam method described here provides a means to calculate the total dose, is the subject of a companion paper.

The presence of heterogeneous media can produce significant perturbations of dose distribution in brachytherapy. In a companion paper, we proposed a dose decomposition approach for dose calculation in a heterogeneous medium, which separately treats dose contributions from primary, once-scattered and multiple-scattered photons. The companion paper also describes and verifies a micro-beam ray-tracing method for evaluating the once-scatter dose. This paper deals with the calculation of the multiple-scatter dose. We present two empirical formulations for evaluating the heterogeneity correction factor for a 27 keV point source in a water sphere containing a disc-shaped heterogeneity. The empirical formulations are based on nonlinear curve fitting of the Monte Carlo multiple-scatter dose estimates calculated for the heterogeneous system. Extensive benchmark comparisons show that these formulations provide results for the multiple-scatter dose that agree within 10% (and mostly within 5%) with corresponding Monte Carlo dose estimates. Combining them with the algorithms for primary and once-scatter dose calculation described in the companion paper yields results for the total dose of equivalent accuracy. The empirical formulations are expressed in simple mathematical forms which involve a separation of the geometry and position variables of the heterogeneous system. Such representation provides a good tool to investigate the heterogeneity-induced perturbation of a multiple-scatter dose at low photon energy.

Interfractional prostate motion during radiotherapy can have deleterious clinical consequences. It has become clinical practice to re-position the patient according to ultrasound or other imaging techniques. We investigated the dosimetric consequences of the linear translational position correction (isocenter correction) when a conformal IMRT technique with nine fields was used. Treatment plans of seven patients with empty and distended rectums were analyzed. The reference plans were calculated on the CT with an empty rectum. The treatment plans were transferred to a second CT with a distended rectum for an uncorrected setup of the patient referenced to bony anatomy and a corrected setup after translational position correction of the isocenter. The dosimetric consequences (with and without correction) were analyzed. For single treatment fractions, organ motion decreased the volume of the prostate encompassed by the 95% isodose (V95%) by up to −24%-p (percentage points). The mean rectum dose increased by up to 41%-p. Linear translational correction increased V95% of the prostate by up to 17%-p while the mean rectum dose was reduced by up to −23%-p compared to the uncorrected setup. Linear translational correction can improve radiation treatment accuracy for prostate cancer if geometrical changes are within certain limits.

The aim of this study was to estimate a plausible α/β ratio for arteriovenous malformations (AVMs) based on reported clinical data, and to design possible fractionation regimens suitable for image-guided intensity-modulated radiation therapy (IG-IMRT) for large AVMs based on the newly obtained α/β ratio. The commonly used obliteration rate (OR) for AVMs with a three year angiographic follow-up from many institutes was fitted to linear-quadratic (LQ) formalism and the Poisson OR model. The determined parameters were then used to calculate possible fractionation regimens for IG-IMRT based on the concept of a biologically effective dose (BED) and an equivalent uniform dose (EUD). The radiobiological analysis yields a α/β ratio of 2.2 ± 1.6 Gy for AVMs. Three sets of possible fractionated schemes were designed to achieve equal or better biological effectiveness than the single-fraction treatments while maintaining the same probability of normal brain complications. A plausible α/β ratio was derived for AVMs and possible fractionation regimens that may be suitable for IG-IMRT for large AVM treatment are proposed. The sensitivity of parameters on the calculation was also studied. The information may be useful to design new clinical trials that use IG-IMRT for the treatment of large AVMs.

Three-dimensional (3D) soft tissue tracking is of interest for monitoring organ motion during therapy. Our goal is to assess the tracking performance of a curvilinear 3D ultrasound probe in terms of the accuracy and precision of measured displacements. The first aim was to examine the depth dependence of the tracking performance. This is of interest because the spatial resolution varies with distance from the elevational focus and because the curvilinear geometry of the transducer causes the spatial sampling frequency to decrease with depth. Our second aim was to assess tracking performance as a function of the spatial sampling setting (low, medium or high sampling). These settings are incorporated onto 3D ultrasound machines to allow the user to control the trade-off between spatial sampling and temporal resolution. Volume images of a speckle-producing phantom were acquired before and after the probe had been moved by a known displacement (1, 2 or 8 mm). This allowed us to assess the optimum performance of the tracking algorithm, in the absence of motion. 3D speckle tracking was performed using 3D cross-correlation and sub-voxel displacements were estimated. The tracking performance was found to be best for axial displacements and poorest for elevational displacements. In general, the performance decreased with depth, although the nature of the depth dependence was complex. Under certain conditions, the tracking performance was sufficient to be useful for monitoring organ motion. For example, at the highest sampling setting, for a 2 mm displacement, good accuracy and precision (an error and standard deviation of <0.4 mm) were observed at all depths and for all directions of displacement. The trade-off between spatial sampling, temporal resolution and size of the field of view (FOV) is discussed.

It is important to assess the viability of extremity soft tissues, as this component is often the determinant of the final outcome of fracture treatment. Microwave tomography (MWT) and sensing might be able to provide a fast and mobile assessment of such properties. MWT imaging of extremities possesses a complicated, nonlinear, high dielectric contrast inverse problem of diffraction tomography. There is a high dielectric contrast between bone and soft tissue in the extremities. A contrast between soft tissue abnormalities is less pronounced when compared with the high bone–soft tissue contrast. The goal of this study was to assess the feasibility of MWT for functional imaging of extremity soft tissues, i.e. to detect a relatively small contrast within soft tissues in closer proximity to high contrast boney areas.

Both experimental studies and computer simulation were performed. Experiments were conducted using live pigs with compromised blood flow and compartment syndrome within an extremity. A whole 2D tomographic imaging cycle at 1 GHz was computer simulated and images were reconstructed using the Newton, MR-CSI and modified Born methods.

Results of experimental studies demonstrate that microwave technology is sensitive to changes in the soft tissue blood content and elevated compartment pressure. It was demonstrated that MWT is feasible for functional imaging of extremity soft tissues, circulatory-related changes, blood flow and elevated compartment pressure.

The issue of setup errors consisting of translation, rotation and deformation components in head and neck radiotherapy is addressed with a piecewise registration of small independent regions on a portal image to their reference position. These rectangular regions are termed featurelets as they contain relevant anatomical features. The resulting displacement vectors of each featurelet reflect both the center-of-mass (COM), i.e. the rigid, and the non-rigid component of the setup error. The displacement vectors of a series of daily portal images were subjected to a principal component analysis. In addition to the mean, systematic displacement of each featurelet, this analysis yields correlated patterns of anatomical deformations. Hence, the physiological movements of an individual patient can be obtained without a biomechanical model. It is shown that in the presence of setup errors that are due to rotations or deformations a correction by the COM displacement may deteriorate the error of parts of the anatomy further. The featurelet analysis can be used to refine setup correction protocols, tune spatially variable setup margins in treatment planning and optimize patient immobilization devices.

Previously we have investigated a depth-independent compensation for collimator detector response (CDR) included in the OSEM reconstruction, intended for SPECT images that have been corrected for scatter and septal penetration using convolution-based methods. In this work, the aim was to study how different filtering strategies affect contrast as a function of noise when using Gaussian smoothing filters in combination with the above-described CDR compensation. The evaluation was performed for ¹²³I dopamine transporter (DAT) SPECT images. Prefiltering with 2D Gaussian filter kernels, where the deterioration in resolution is included in the depth-independent CDR compensation, was compared to conventional postfiltering with 3D Gaussian filter kernels. Images reconstructed without filtering are also included in the comparison. It was found that there is little benefit in noise reduction when using CDR compensation. However, this variant of prefiltering gives consistently higher contrasts as a function of noise compared with the postfiltering alternative, and that could be of interest when using other types of filters with contrast improving properties.

A method of four-dimensional (4D) magnetic resonance imaging (MRI) has been implemented and evaluated. It consists of retrospective sorting and slice stacking of two-dimensional (2D) images using an external signal for motion monitoring of the object to be imaged. The presented method aims to determine the tumour trajectories based on a signal that is appropriate for monitoring the movement of the target volume during radiotherapy such that the radiation delivery can be adapted to the movement. For evaluation of the 4D-MRI method, it has been applied to a dynamic lung phantom, which exhibits periodic respiratory movement of a porcine heart–lung explant with artificial pulmonary nodules. Anatomic changes of the lung phantom caused by respiratory motion have been quantified, revealing hysteresis. The results demonstrate the feasibility of the presented method of 4D-MRI. In particular, it enables the determination of trajectories of periodically moving objects with an uncertainty in the order of 1 mm.

Recently, x-ray differential phase contrast computed tomography (DPC-CT) has been experimentally implemented using a conventional source combined with several gratings. Images were reconstructed using a parallel-beam reconstruction formula. However, parallel-beam reconstruction formulae are not directly applicable for a large image object where the parallel-beam approximation fails. In this note, we present a new image reconstruction formula for fan-beam DPC-CT. There are two major features in this algorithm: (1) it enables the reconstruction of a local region of interest (ROI) using data acquired from an angular interval shorter than 180°+ fan angle and (2) it still preserves the filtered backprojection structure. Numerical simulations have been conducted to validate the image reconstruction algorithm.